Method of purifying macrolides

a macrolide and purification technology, applied in the field of purification methods, can solve the problems of undesirable impurities in pharmaceutical compounds, and achieve the effect of reducing the level of impurities and reducing impurities

Inactive Publication Date: 2007-05-22
TEVA PHARM USA INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0009]In one aspect, the present invention relates to a method of separating impurities from (i.e. reducing the level of impurities in) a macrolide, especially tacrolimus, ascomycin, sirolimus (rapamycin), everolimus, and pimecrolimus. The method includes the steps of: preparing a loading charge of a macrolide; loading the loading charge onto a bed of wet sorption resin; eluting the bed with an eluent that contains THF or acetonitrile, water, and optionally an additional organic solvent; collecting a main fraction (heart cut) of eluent, and isolating the macrolide having reduced impurities from the main fraction.

Problems solved by technology

Presence of impurities in a pharmaceutical compound is undesirable, and health authorities in many jurisdictions (e.g. the Food and Drug Administration in the United States) have established guidelines relating to acceptable levels of impurities in pharmaceuticals.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

[0059]Area percents refer to area percent of HPLC chromatograms obtained by the hereinabove described method.

[0060]The procedure below was carried-out at 28° C. to 32° C.

[0061]A bed of sorption resin (Amberlite® XAD 1180) in a column (45 cm diameter) using water:THF to charge the column (ca. 100 L wet sorption resin) was prepared.

[0062]Water (86 L) was slowly added, with agitation, to a solution of tacrolimus (1227 g) in acetonitrile (10 L) in which sorption resin (Amberlite® XAD 1180; 9 L) was suspended with stirring. The tacrolimus used contained about 2.6 area-% RRT0.95 and about 2.9 area-% RRT1.25. When the addition of water was complete, the loading charge of sorption resin was collected by filtration.

[0063]The collected loading charge was loaded (juxtaposed) as a layer on top of the bed of wet sorption resin.

[0064]The column was first eluted with ca. 1800 L of a first eluent made-up of THF / water (33 vol-% THF). The column was then eluted with second eluent made-up of THF / water...

example 2

[0068]The general procedure of example 1 was repeated to investigate the effect of eluent composition and flow rate.

[0069]Through these experiments, we could establish that elution flow rate reduction increases the separation efficiency of the chromatography. Increasing the elution flow rate reduced the efficiency of the chromatography. Flow rate of 25 cm / cm2.hour (instead of 6.9 –8.2 cm / cm2.hour) resulted in significant reductionb in efficiency, but main fraction of having the quality of that described in Example 1 could be collected.

[0070]It was further established that first eluent of 34% by volume THF (instead of 33% by volume) increased the yield of chromatography. The yield was 69%. Impurity RRT:0.95 level of main fraction was 0.10 area %.

[0071]When an eluent having 31 vol-% THF was used, elution time of tacrolimus was increased. The mentioned eluent concentrations (31%, 33%, 34%, 40% by volume tetrahydrofuran) were found usable for elution of tacrolimus, without increasing of...

example 3

[0073]Area percents refer to area percent of HPLC chromatograms obtained by the hereinabove described method.

[0074]The procedure below was carried out at 20° C. to 25° C.

[0075]A bed of sorption resin (Diaion SP 207) in a column (3.2 cm diameter) using water to charge the column (ca. 550 mL wet sorption resin) was prepared.

[0076]Tacrolimus (7.2 g) was dissolved in a mixture of acetonitrile (30 mL) and water (20 mL). The tacrolimus contained about 2.6 area-% RRT0.95 (ascomycin) and about 2.9 area-% RRT1.25 (dihydrotacrolimus).

[0077]The tacrolimus solution was loaded as layer on top of the bed of wet sorption resin.

[0078]The column was eluted with ca. 8 L of eluent made up of acetonitrile / water / phosphoric acid (600:400:1). The elution rate was 90 mL / hour.

[0079]Fractions 32–45 were combined. The combined fractions contained 1.9 g of tacrolimus. The impurity content of the combined fractions was about 2.9 area-% RRT0.95 (ascomycin) and about 1.2 area-% RRT1.25 (dihydrotacrolimus).

[0080]T...

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Abstract

Provided is a method of purifying a macrolide, especially tacrolimus, that includes loading macrolide onto a bed of sorption resin and elting with a suitable eluent such as a combination of water and tetrahydrofuran.

Description

RELATED APPLICATIONS[0001]This application claims the benefits of U.S. provisional application Ser. No. 60 / 490,070, filed Jul. 24, 2003 and U.S. provisional application Ser. No. 60 / 539,363, filed Jan. 26, 2004, the contents of all of which are incorporated herein by reference.[0002]The present invention relates to a method of purifying macrolides, especially tacrolimus, ascomycin, sirolimus, everolimus, or pimecrolimus, by a separation method using sorption resins.BACKGROUND OF THE INVENTION[0003]Macrolides are multi-membered lactone rings having one or more deoxy sugars as substituents. Erythromycin, azithromycin, and clarithromycin are macrolides that have bacteriostatic and / or bactericidal activity.[0004]Tacrolimus (FK 506) is also a macrolide antibiotic that is also an immunosuppressive agent. More potent than cyclosporin, tacrolimus reportedly has a selective inhibitory effect on T-lymphocytes.[0005]Pimecrolimus is a macrolactam and a ascomycin derivative that reportedly inhibi...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): B01D15/08C07D498/18
CPCC07D498/18G01N30/02C07H17/08
Inventor KERI, VILMOSCZOVEK, ZOLTANCSORVASI, ANDREARANTAL, FERENC
Owner TEVA PHARM USA INC
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